Variant Synonymizer: Platform to identify mutations defined in different ways is available now!

VarSy

Over 2,000 gene–disease validation summaries are now available—no login required!

Browse Summaries

RERE – Neurodevelopmental Disorder with or without Anomalies of the Brain, Eye, or Heart

Heterozygous de novo variants in RERE underlie an autosomal dominant neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH) (PMID:29330883). Nine unrelated probands were reported with partial deletions or deleterious sequence variants confirmed to be de novo in all cases with parental testing ([PMID:29330883]).

Variants include missense and loss-of-function changes clustered in the conserved Atrophin-1 domain, with five distinct missense substitutions and a single-base duplication leading to a frameshift. A representative allele is c.142A>G (p.Lys48Glu) ([PMID:29330883]). High-frequency alterations in a histidine-rich region, including a recurrent two–amino-acid duplication, correlate with a CHARGE‐like presentation.

No familial segregation beyond de novo events was observed. All nine probands arose sporadically, yielding zero additional affected relatives with segregating variants.

Experimental evidence from a zebrafish rerea mutant recapitulates optic fissure closure defects due to deregulated SHH signaling and demonstrates rescue of coloboma by the SHH inhibitor HPI-1, confirming a loss-of-function mechanism. Human RERE hypomorphic variants show impaired repression of SHH signaling and abnormal nuclear localization in cell assays ([PMID:36576487]).

Integration of clinical and experimental data supports a strong gene–disease association with clear genotype–phenotype correlations that inform surveillance for structural eye, cardiac, renal, and auditory anomalies and guide screening in CHARGE‐like cases. Key take-home: RERE variant analysis provides actionable risk stratification and informs targeted management in NEDBEH.

References

  • Human Mutation • 2018 • Genotype-phenotype correlations in individuals with pathogenic RERE variants. PMID:29330883
  • Developmental Dynamics • 2023 • Zebrafish model of RERE syndrome recapitulates key ophthalmic defects that are rescued by small molecule inhibitor of shh signaling. PMID:36576487

Evidence Based Scoring (AI generated)

Gene–Disease Association

Strong

Nine de novo probands with consistent phenotype and genotype–phenotype correlations, supported by parental testing ([PMID:29330883]).

Genetic Evidence

Strong

Nine unrelated de novo variants confirmed by segregation analysis, including five missense and one frameshift allele affecting Atrophin-1 domain.

Functional Evidence

Moderate

Zebrafish rerea mutant recapitulates human ocular defects with rescue by SHH inhibition and cell assays demonstrate hypomorphic repression of SHH signaling ([PMID:36576487]).